Tyrosine kinase inhibitors

ABSTRACT

The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to compounds which inhibit,regulate and/or modulate tyrosine kinase signal transduction,compositions which contain these compounds, and methods of using them totreat tyrosine kinase-dependent diseases and conditions, such asangiogenesis, cancer, tumor growth, atherosclerosis, age related maculardegeneration, diabetic retinopathy, inflammatory diseases, and the likein mammals.

[0002] Tyrosine kinases are a class of enzymes that catalyze thetransfer of the terminal phosphate of adenosine triphosphate to tyrosineresidues in protein substrates. Tyrosine kinases are believed, by way ofsubstrate phosphorylation, to play critical roles in signal transductionfor a number of cell functions. Though the exact mechanisms of signaltransduction is still unclear, tyrosine kinases have been shown to beimportant contributing factors in cell proliferation, carcinogenesis andcell differentiation.

[0003] Tyrosine kinases can be categorized as receptor type ornon-receptor type. Receptor type tyrosine kinases have an extracellular,a transmembrane, and an intracellular portion, while non-receptor typetyrosine kinases are wholly intracellular.

[0004] The receptor-type tyrosine kinases are comprised of a largenumber of transmembrane receptors with diverse biological activity. Infact, about 20 different subfamilies of receptor-type tyrosine kinaseshave been identified. One tyrosine kinase subfamily, designated the HERsubfamily, is comprised of EGFR, HER2, HER3, and HER4. Ligands of thissubfamily of receptors include epithileal growth factor, TGF-α,amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily ofthese receptor-type tyrosine kinases is the insulin subfamily, whichincludes INS-R, IGF-IR, and IR-R. The PDGF subfamily includes the PDGF-αand β receptors, CSFIR, c-kit and FLK-II. Then there is the FLK familywhich is comprised of the kinase insert domain receptor (KDR), fetalliver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-liketyrosine kinase-1 (flt-1). The PDGF and FLK families are usuallyconsidered together due to the similarities of the two groups. For adetailed discussion of the receptor-type tyrosine kinases, see Plowmanet al., DN&P 7(6):334-339, 1994, which is hereby incorporated byreference.

[0005] The non-receptor type of tyrosine kinases is also comprised ofnumerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps,Fak, Jak, Ack, and LIMK. Each of these subfamilies is furthersub-divided into varying receptors. For example, the Src subfamily isone of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr,and Yrk. The Src subfamily of enzymes has been linked to oncogenesis.For a more detailed discussion of the non-receptor type of tyrosinekinases, see Bolen Oncogene, 8:2025-2031 (1993), which is herebyincorporated by reference.

[0006] Both receptor-type and non-receptor type tyrosine kinases areimplicated in cellular signaling pathways leading to numerous pathogenicconditions, including cancer, psoriasis and hyperimmune responses.

[0007] Several receptor-type tyrosine kinases, and the growth factorsthat bind thereto, have been suggested to play a role in angiogenesis,although some may promote angiogenesis indirectly (Mustonen and Alitalo,J. Cell Biol. 129:895-898, 1995). One such receptor-type tyrsoine kinaseis fetal liver kinase 1 or FLK-1. The human analog of FLK-1 is thekinase insert domain-containing receptor KDR, which is also known asvascular endothelial cell growth factor receptor 2 or VEGFR-2, since itbinds VEGF with high affinity. Finally, the murine version of thisreceptor has also been called NYK (Oelrichs et al., Oncogene 8(1):11-15,1993). VEGF and KDR are a ligand-receptor pair that play an importantrole in the proliferation of vascular endothelial cells, and theformation and sprouting of blood vessels, termed vasculogenesis andangiogenesis, respectively.

[0008] Angiogenesis is characterized by excessive activity of vascularendothelial growth factor (VEGF). VEGF is actually comprised of a familyof ligands (Klagsbum and D'Amore, Cytokine &Growth Factor Reviews7:259-270, 1996). VEGF binds the high affinity membrane-spanningtyrosine kinase receptor KDR and the related fms-like tyrosine kinase-1,also known as Flt-1 or vascular endothelial cell growth factor receptor1 (VEGFR-1). Cell culture and gene knockout experiments indicate thateach receptor contributes to different aspects of angiogenesis. KDRmediates the mitogenic function of VEGF whereas Flt-1 appears tomodulate non-mitogenic functions such as those associated with cellularadhesion. Inhibiting KDR thus modulates the level of mitogenic VEGFactivity. In fact, tumor growth has been shown to be susceptible to theantiangiogenic effects of VEGF receptor antagonists. (Kim et al., Nature362, pp. 841-844, 1993).

[0009] Solid tumors can therefore be treated by tyrosine kinaseinhibitors since these tumors depend on angiogenesis for the formationof the blood vessels necessary to support their growth. These solidtumors include histiocytic lymphoma, cancers of the brain, genitourinarytract, lymphatic system, stomach, larynx and lung, including lungadenocarcinoma and small cell lung cancer. Additional examples includecancers in which overexpression or activation of Raf-activatingoncogenes (e.g., K-ras, erb-B) is observed. Such cancers includepancreatic and breast carcinoma. Accordingly, inhibitors of thesetyrosine kinases are useful for the prevention and treatment ofproliferative diseases dependent on these enzymes.

[0010] The angiogenic activity of VEGF is not limited to tumors. VEGFaccounts for most of the angiogenic activity produced in or near theretina in diabetic retinopathy. This vascular growth in the retina leadsto visual degeneration culminating in blindness. Ocular VEGF mRNA andprotein are elevated by conditions such as retinal vein occlusion inprimates and decreased pO₂ levels in mice that lead toneovascularization. Intraocular injections of anti-VEGF monoclonalantibodies or VEGF receptor immunofusions inhibit ocularneovascularization in both primate and rodent models. Regardless of thecause of induction of VEGF in human diabetic retinopathy, inhibition ofocular VEGF is useful in treating the disease.

[0011] Expression of VEGF is also significantly increased in hypoxicregions of animal and human tumors adjacent to areas of necrosis. VEGFis also upregulated by the expression of the oncogenes ras, raf, src andmutant p53 (all of which are relevant to targeting cancer). Monoclonalanti-VEGF antibodies inhibit the growth of human tumors in nude mice.Although these same tumor cells continue to express VEGF in culture, theantibodies do not diminish their mitotic rate. Thus tumor-derived VEGFdoes not function as an autocrine mitogenic factor. Therefore, VEGFcontributes to tumor growth in vivo by promoting angiogenesis throughits paracrine vascular endothelial cell chemotactic and mitogenicactivities. These monoclonal antibodies also inhibit the growth oftypically less well vascularized human colon cancers in athymic mice anddecrease the number of tumors arising from inoculated cells.

[0012] Viral expression of a VEGF-binding construct of Flk-1, Flt-1, themouse KDR receptor homologue, truncated to eliminate the cytoplasmictyrosine kinase domains but retaining a membrane anchor, virtuallyabolishes the growth of a transplantable glioblastoma in mice presumablyby the dominant negative mechanism of heterodimer formation withmembrane spanning endothelial cell VEGF receptors. Embryonic stem cells,which normally grow as solid tumors in nude mice, do not producedetectable tumors if both VEGF alleles are knocked out. Taken together,these data indicate the role of VEGF in the growth of solid tumors.Inhibition of KDR or Flt-1 is implicated in pathological angiogenesis,and these receptors are useful in the treatment of diseases in whichangiogenesis is part of the overall pathology, e.g., inflammation,diabetic retinal vascularization, as well as various forms of cancersince tumor growth is known to be dependent on angiogenesis. (Weidner etal., N. Engl. J. Med., 324, pp. 1-8, 1991).

[0013] Accordingly, the identification of small compounds whichspecifically inhibit, regulate and/or modulate the signal transductionof tyrosine kinases is desirable and is an object of this invention.

SUMMARY OF THE INVENTION

[0014] The present invention relates to compounds that are capable ofinhibiting, modulating and/or regulating signal transduction of bothreceptor-type and non-receptor type tyrosine kinases. One embodiment ofthe present invention is illustrated by a compound of Formula I, and thepharmaceutically acceptable salts and stereoisomers thereof:

DETAILED DESCRIPTION OF THE INVENTION

[0015] The compounds of this invention are useful in the inhibition ofkinases and are illustrated by a compound of Formula I:

[0016] or a pharmaceutically acceptable salt or stereoisomer thereof,wherein

[0017] Q is S,O, or —E═D—;

[0018] is selected from the following:

[0019] a is or 1;

[0020] b is or 1;

[0021] s is 1 or 2;

[0022] m is 0, 1, or 2;

[0023] E═D is C═N, N═C, or C═C;

[0024] R¹, R^(1a), R⁴ and R⁵ are independently selected from:

[0025] 1) H,

[0026] 2) (C═O)_(a)O_(b)C₋C₁₀ alkyl, optionally substituted with one tothree substituents selected from R⁶,

[0027] 3) (C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R⁶,

[0028] 4) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl, optionally substituted with oneto three substituents selected from R⁶,

[0029] 5) (C═O)_(a)O_(b)C₂-C₁₀ alkynyl, optionally substituted with oneto three substituents selected from R⁶,

[0030] 6) SO_(m)C₁-C₁₀ alkyl, optionally substituted with one to threesubstituents selected from R⁶,

[0031] 7) SO_(m)aryl, optionally substituted with one to threesubstituents selected from R⁶,

[0032] 8) CO₂H,

[0033] 9) halo,

[0034] 10) CN,

[0035] 11) OH,

[0036] 12) O_(b)C₁-C₆ perfluoroalkyl, and

[0037] 13) (C═O)_(a)NR⁷R⁸;

[0038] R² and R³ are independently selected from the group consistingof:

[0039] 1) H,

[0040] 2) (C═O)O_(a)C₁-C₁₀ alkyl,

[0041] 3) (C═O)O_(a)aryl,

[0042] 4) C₁-C₁₀ alkyl,

[0043] 5) SO_(m)C₁-C₁₀ alkyl,

[0044] 6) SO_(m)aryl,

[0045] 7) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl,

[0046] 8) (C═O)_(a)O_(b)C₂-C₁₀ alkynyl, and

[0047] 9) aryl,

[0048] said alkyl, aryl, alkenyl and alkynyl is optionally substitutedwith one to three substituents selected from R⁶;

[0049] R^(4a) is selected from the group consisting of:

[0050] 1) (C═O)O_(a)C₁-C₁₀ alkyl,

[0051] 2) (C═O)O_(a) aryl,

[0052] 3) C₁-C₁₀ alkyl,

[0053] 4) SO_(m)C₁-C₁₀ alkyl,

[0054] 5) SO_(m)aryl,

[0055] 6) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl,

[0056] 7) (C═O)_(a)O_(b)C₂-C₁₀ alkynyl, and

[0057] 8) aryl,

[0058] said alkyl, aryl, alkenyl and alkynyl is optionally substitutedwith one to three substituents selected from R⁶;

[0059] R⁶ is:

[0060] 1) H,

[0061] 2) (C═O)_(a)O_(b)C₁-C₆ alkyl,

[0062] 3) (C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a),

[0063] 4) C₂-C₁₀ alkenyl,

[0064] 5) C₂-C₁₀ alkynyl,

[0065] 6) heterocyclyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0066] 7) CO₂H,

[0067] 8) halo,

[0068] 9) CN,

[0069] 10) OH,

[0070] 11) oxo,

[0071] 12) O_(b)C₁-C₆ perfluoroalkyl, or

[0072] 13) NR⁷R⁸;

[0073] R^(6a) is:

[0074] 1) H,

[0075] 2) SO_(m)aryl,

[0076] 3) SO_(m)C₁-C₆ alkyl,

[0077] 4) (C═O)_(a)O_(b)C₁-C₆ alkyl,

[0078] 5) (C═O)_(a)O_(b)aryl,

[0079] 6) C₂-C₁₀ alkenyl,

[0080] 7) C₂-C₁₀ alkynyl,

[0081] 8) heterocyclyl,

[0082] 9) CO₂H,

[0083] 10) halo,

[0084] 11) CN,

[0085] 12) OH,

[0086] 13) oxo,

[0087] 14) O_(b)C₁-C₆ perfluoroalkyl, or

[0088] 15) N(C₁-C₆ alkyl)₂;

[0089] R⁷ and R⁸ are independently selected from:

[0090] 1) H,

[0091] 2) (C═O)O_(b)C₁-C₁₀ optionally substituted with one to threesubstituents selected from R^(6a),

[0092] 3) (C═O)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a),

[0093] 4) C₁-C₁₀ alkyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0094] 5) aryl, optionally substituted with one to three substituentsselected from R^(6a),

[0095] 6) C₂-C₁₀ alkenyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0096] 7) C₂-C₁₀ alkynyl, optionally substituted with one to threesubstituents selected from R^(6a), and

[0097] 8) heterocyclyl, or

[0098] R⁷ and R⁸ can be taken together with the nitrogen to which theyare attached to form a 5-7 membered heterocycle containing, in additionto the nitrogen, one or two additional heteroatoms selected from N, 0and S, said heterocycle optionally substituted with one to threesubstituents selected from R^(6a).

[0099] A second embodiment is illustrated by the compound of Formula I,as described above, wherein Q is E═D. In a third embodiment, E═D isfurther defined as C═C.

[0100] A fourth embodiment of the invention is the compound of FormulaI, as described above, wherein Q is E═D; E═D is C═C;

[0101] R¹, R^(1a), R⁴ and R⁵ are independently selected from:

[0102] 1) H,

[0103] 2) (C═O)_(a)O_(b)C₁-C₆ alkyl, optionally substituted with one tothree substituents selected from R⁶,

[0104] 3) (C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R⁶,

[0105] 4) (C═O)_(a)O_(b)C₂-C₆ alkenyl, optionally substituted with oneto three substituents selected from R⁶,

[0106] 5) CO₂H,

[0107] 6) halo,

[0108] 7) CN,

[0109] 8) OH,

[0110] 9) O_(b)C₁-C₃ perfluoroalkyl, and

[0111] 10) (C═O)_(a)NR⁷R⁸;

[0112] R² and R³ are independently selected from the group consistingof: 1) H,

[0113] 2) (C═O)O_(a)C₁-C₆ alkyl, and

[0114] 3) C₁-C₆ alkyl;

[0115] R^(4a) is (C═O)O_(a)C₁-C₆ alkyl or C₁-C₆ alkyl;

[0116] R⁶ is:

[0117] 1) H,

[0118] 2) (C═O)_(a)O_(b)C₁-C₆ alkyl,

[0119] 3) (C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a),

[0120] 4) C₂-C₆ alkenyl,

[0121] 5) heterocyclyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0122] 6) CO₂H,

[0123] 7) halo,

[0124] 8) CN,

[0125] 9) OH,

[0126] 10) oxo,

[0127] 11) O_(b)C₁-C₃ perfluoroalkyl, or

[0128] 12) NR⁷R⁸;

[0129] R^(6a) is:

[0130] 1) H,

[0131] 2) SO_(m)aryl,

[0132] 3) SO_(m)C₁-C₆ alkyl,

[0133] 4) (C═O)_(a)O_(b)C₁-C₆ alkyl,

[0134] 5) (C═O)_(a)O_(b)aryl,

[0135] 6) C₂-C₆ alkenyl,

[0136] 7) heterocyclyl,

[0137] 8) CO₂H,

[0138] 9) halo,

[0139] 10) CN,

[0140] 11) OH,

[0141] 12) oxo,

[0142] 13) O_(b)C₁-C₃ perfluoroalkyl, or

[0143] 14) N(C₁-C₆ alkyl)₂;

[0144] R⁷ and R⁸ are independently selected from:

[0145] 1) H,

[0146] 2) (C═O)O_(b)C₁-C₆ alkyl, optionally substituted with one tothree substituents selected from R^(6a).

[0147] 3) (C═O)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a),

[0148] 4) C₁-C₆ alkyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0149] 5) aryl, optionally substituted with one to three substituentsselected from R^(6a),

[0150] 6) C₂-C₆ alkenyl, optionally substituted with one to threesubstituents selected from R^(6a), and

[0151] 7) heterocyclyl, or

[0152] R⁷ and R⁸ can be taken together with the nitrogen to which theyare attached to form a 5-7 membered heterocycle containing, in additionto the nitrogen, one or two additional heteroatoms selected from N, Oand S, said heterocycle optionally substituted with one to threesubstituents selected from R^(6a).

[0153] In a fifth embodiment of the invention, the compound of Formula Iis defined such that Q is E═D; E═D is C═C;

[0154] a is 0 or 1;

[0155] b is 0 or 1;

[0156] s is 1;

[0157] R¹ and R⁴ are independently selected from:

[0158] 1) H,

[0159] 2) (C═O)_(a)O_(b)C₁-C₆ alkyl, optionally substituted with one tothree substituents selected from R⁶,

[0160] 3) (C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R⁶,

[0161] 4) (C═O)_(a)O_(b)C₂-C₆ alkenyl, optionally substituted with oneto three substituents selected from R⁶,

[0162] 5) (C═O)_(a)O_(b)C₂-C₆ alkynyl, optionally substituted with oneto three substituents selected from R⁶,

[0163] 6) CO₂H,

[0164] 7) halo,

[0165] 8) CN,

[0166] 9) OH,

[0167] 10) O_(b)C₁-C₃ perfluoroalkyl, and

[0168] 11) (C═O)_(a)NR⁷R⁸;

[0169] R² and R³ are independently selected from H and methyl;

[0170] R^(4a) is methyl;

[0171] R⁵ and R^(1a) are H;

[0172] R⁶ is:

[0173] 1) H,

[0174] 2) (C═O)_(a)O_(b)C₁-C₆ alkyl,

[0175] 3) (C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a),

[0176] 4) C₂-C₁₀ alkenyl,

[0177] 5) C₃-C₁₀ alkynyl,

[0178] 6) heterocyclyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0179] 7) CO₂H,

[0180] 8) halo,

[0181] 9) CN,

[0182] 10) OH,

[0183] 11) oxo,

[0184] 12) O_(b)C₁-C₃ perfluoroalkyl, or

[0185] 13) NR⁷R⁸;

[0186] R^(6a) is:

[0187] 1) H,

[0188] 2) SO_(m)aryl,

[0189] 3) SO_(m)C₁-C₆ alkyl,

[0190] 4) (C═O)_(a)O_(b)C₁-C₆ alkyl,

[0191] 5) (C═O)_(a)O_(b)aryl,

[0192] 6) C₂-C₁₀ alkenyl,

[0193] 7) C₂-C₁₀ alkynyl,

[0194] 8) heterocyclyl,

[0195] 9) CO₂H,

[0196] 10) halo,

[0197] 11) CN,

[0198] 12) OH,

[0199] 13) oxo,

[0200] 14) O_(b)C₁-C₃ perfluoroalkyl, or

[0201] 15) N(C₁-C₆ alkyl)₂;

[0202] R⁷ and R⁸ are independently selected from:

[0203] 1) H,

[0204] 2) (C═O)O_(b)C₁-C₆ alkyl, optionally substituted with one tothree substituents selected from R^(6a),

[0205] 3) (C═O)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a),

[0206] 4) C₁-C₁₀ alkyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0207] 5) aryl, optionally substituted with one to three substituentsselected from R^(6a),

[0208] 6) C₂-C₆ alkenyl, optionally substituted with one to threesubstituents selected from R^(6a),

[0209] 7) C₂-C₆ alkynyl, optionally substituted with one to threesubstituents selected from R^(6a), and

[0210] 8) heterocyclyl, or

[0211] R⁷ and R⁸ can be taken together with the nitrogen to which theyare attached to form a piperidinyl, piperazinyl, morpholinyl orpyrrolidinyl group, optionally substituted with one or two substituentsselected from R^(6a).

[0212] Yet another embodiment of the present invention is a compoundwhich is3-(4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-oneor a pharmaceutically acceptable salt or stereoisomer thereof.

[0213] Also included within the scope of the present invention is apharmaceutical composition which is comprised of a compound of Formula Ias described above and a pharmaceutically acceptable carrier. Thepresent invention also encompasses a method of treating or preventingcancer in a mammal in need of such treatment which is comprised ofadministering to said mammal a therapeutically effective amount of acompound of Formula I. Preferred cancers for treatment are selected fromcancers of the brain, genitourinary tract, lymphatic system, stomach,larynx and lung. Another set of preferred forms of cancer arehistiocytic lymphoma, lung adenocarcinoma, small cell lung cancers,pancreatic cancer, gioblastomas and breast carcinoma.

[0214] Also included is a method of treating or preventing a disease inwhich angiogenesis is implicated, which is comprised of administering toa mammal in need of such treatment a therapeutically effective amount ofa compound of Formula I. Such a disease in which angiogenesis isimplicated is ocular diseases such as retinal vascularization, diabeticretinopathy, age-related macular degeneration, and the like.

[0215] Also included within the scope of the present invention is amethod of treating or preventing inflammatory diseases which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of Formula I. Examples of suchinflammatory diseases are rheumatoid arthritis, psoriasis, contactdermatitis, delayed hypersensitivity reactions, and the like.

[0216] Also included is a method of treating or preventing a tyrosinekinase-dependent disease or condition in a mammal which comprisesadministering to a mammalian patient in need of such treatment atherapeutically effective amount of a compound of Formula I. Thetherapeutic amount varies according to the specific disease and isdiscemable to the skilled artisan without undue experimentation.

[0217] A method of treating or preventing retinal vascularization whichis comprised of administering to a mammal in need of such treatment atherapeutically effective amount of compound of Formula I is alsoencompassed by the present invention. Methods of treating or preventingocular diseases, such as diabetic retinopathy and age-related maculardegeneration, are also part of the invention. Also included within thescope of the present invention is a method of treating or preventinginflammatory diseases, such as rheumatoid arthritis, psoriasis, contactdermatitis and delayed hypersensitivity reactions, as well as treatmentor prevention of bone associated pathologies selected from osteosarcoma,osteoarthritis, and rickets.

[0218] The invention also contemplates the use of the instantly claimedcompounds in combination with a second compound selected from:

[0219] 1) an estrogen receptor modulator,

[0220] 2) an androgen receptor modulator,

[0221] 3) retinoid receptor modulator,

[0222] 4) a cytotoxic agent,

[0223] 5) an antiproliferative agent,

[0224] 6) a prenyl-protein transferase inhibitor,

[0225] 7) an HMG-CoA reductase inhibitor,

[0226] 8) an HIV protease inhibitor,

[0227] 9) a reverse transcriptase inhibitor, and

[0228] 10) another angiogenesis inhibitor.

[0229] Preferred angiogenesis inhibitors are selected from the groupconsisting of a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-a,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, and an antibody to VEGF. Preferred estrogen receptormodulators are tamoxifen and raloxifene.

[0230] Also included in the scope of the claims is a method of treatingcancer which comprises administering a therapeutically effective amountof a compound of Formula I in combination with radiation therapy and/orin combination with a compound selected from:

[0231] 1) an estrogen receptor modulator,

[0232] 2) an androgen receptor modulator,

[0233] 3) retinoid receptor modulator,

[0234] 4) a cytotoxic agent,

[0235] 5) an antiproliferative agent,

[0236] 6) a prenyl-protein transferase inhibitor,

[0237] 7) an HMG-CoA reductase inhibitor,

[0238] 8) an HIV protease inhibitor,

[0239] 9) a reverse transcriptase inhibitor, and

[0240] 10) another angiogenesis inhibitor.

[0241] And yet another embodiment of the invention is a method oftreating cancer which comprises administering a therapeuticallyeffective amount of a compound of Formula I in combination withpaclitaxel or trastuzumab.

[0242] Also within the scope of the invention is a method of reducing orpreventing tissue damage following a cerebral ischemic event whichcomprises administering a therapeutically effective amount of a compoundof Formula I.

[0243] Another embodiment of the invention is a method of treating orpreventing cancer which comprises administering a therapeuticallyeffective amount of a compound of Formula I in combination with a COX-2inhibitor.

[0244] These and other aspects of the invention will be apparent fromthe teachings contained herein.

[0245] “Tyrosine kinase-dependent diseases or conditions” refers topathologic conditions that depend on the activity of one or moretyrosine kinases. Tyrosine kinases either directly or indirectlyparticipate in the signal transduction pathways of a variety of cellularactivities including proliferation, adhesion and migration, anddifferentiation. Diseases associated with tyrosine kinase activitiesinclude the proliferation of tumor cells, the pathologicneovascularization that supports solid tumor growth, ocularneovascularization (diabetic retinopathy, age-related maculardegeneration, and the like) and inflammation (psoriasis, rheumatoidarthritis, and the like).

[0246] The compounds of the present invention may have asymmetriccenters, chiral axes, and chiral planes (as described in: E. L. Elieland S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley &Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemicmixtures, and as individual diastereomers, with all possible isomers andmixtures thereof, including optical isomers, being included in thepresent invention. In addition, the compounds disclosed herein may existas tautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof.

[0247] When any variable (e.g. aryl, heterocycle, R¹, R² etc.) occursmore than one time in any constituent, its definition on each occurrenceis independent at every other occurrence. Also, combinations ofsubstituents and variables are permissible only if such combinationsresult in stable compounds. Lines drawn into the ring systems fromsubstituents (such as from R¹, R², R³, R⁴ etc.) indicate that theindicated bond may be attached to any of the substitutable ring carbonatoms. If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.For example,

[0248] can be, inter alia, any of the following when:

[0249] X and Z are C,

[0250] Y is N,

[0251] R⁵ is CH₃,

[0252] R³ is H, and

[0253] (R⁴)_(t) is as defined in the claims:

[0254] It is understood that substituents and substitution patterns onthe compounds of the instant invention can be selected by one ofordinary skill in the art to provide compounds that are chemicallystable and that can be readily synthesized by techniques known in theart, as well as those methods set forth below, from readily availablestarting materials.

[0255] As used herein, “alkyl” is intended to include both branched,straight-chain, and cyclic saturated aliphatic hydrocarbon groups havingthe specified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear, branched, or cyclic arrangement. For example,“C₁-C₁₀ alkyl” specifically includes methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on, as well ascycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,tetrahydro-naphthalene, methylenecylohexyl, and so on. “Alkoxy”represents an alkyl group of indicated number of carbon atoms attachedthrough an oxygen bridge.

[0256] If no number of carbon atoms is specified, the term “alkenyl”refers to a non-aromatic hydrocarbon radical, straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon double bond. Preferably one carbon to carbon double bond ispresent, and up to 4 non-aromatic carbon-carbon double bonds may bepresent. Thus, “C₂-C₆ alkenyl” means an alkenyl radical having from 2 to6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl andcyclohexenyl. As described above with respect to alkyl, the straight,branched or cyclic portion of the alkenyl group may contain double bondsand may be substituted if a substituted alkenyl group is indicated.

[0257] The term “alkynyl” refers to a hydrocarbon radical straight,branched or cyclic, containing from 2 to 10 carbon atoms and at leastone carbon to carbon triple bond. Up to 3 carbon-carbon triple bonds maybe present. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl and butynyl.As described above with respect to alkyl, the straight, branched orcyclic portion of the alkynyl group may contain triple bonds and may besubstituted if a substituted alkynyl group is indicated.

[0258] As used herein, “aryl” is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 atoms in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthrylor acenaphthyl. In cases where the aryl substituent is bicyclic and onering is non-aromatic, it is understood that attachment is via thearomatic ring.

[0259] The term heteroaryl, as used herein, represents a stablemonocyclic or bicyclic ring of up to 7 atoms in each ring, wherein atleast one ring is aromatic and contains from 1 to 4 heteroatoms selectedfrom the group consisting of 0, N and S. Heteroaryl groups within thescope of this definition include but are not limited to: acridinyl,carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl,benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl,quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. Incases where the heteroaryl substituent is bicyclic and one ring isnon-aromatic or contains no heteroatoms, it is understood thatattachment is via the aromatic ring or via the heteroatom containingring, respectively.

[0260] As appreciated by those of skill in the art, “halo” or “halogen”as used herein is intended to include chloro, fluoro, bromo and iodo.The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 5- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof.

[0261] The pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed, e.g., from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like.

[0262] In certain instances, R⁷ and R⁸ are defined such that they can betaken together with the nitrogen to which they are attached to form a5-7 membered heterocycle containing, in addition to the nitrogen, one ortwo additional heteroatoms selected from N, O and S, said heterocycleoptionally substituted with one to three substituents selected fromR^(6a). Examples of the 5-7 membered ring systems that can thus beformed include, but are not limited to the following:

[0263] Preferably is E═D and E═D is C═C.

[0264] Preferably R¹ is H, C₁-C₆ alkyl, or aryl. Most preferably R¹ is Hor C₁-C₂ alkyl.

[0265] The preferred definition of R^(1a) is H.

[0266] Preferably R² and R³ are independently H, C₁-C₆ alkyl, or(C═O)C₁-C₆ alkyl. Most preferably R² and R³ are independently H or C₁-C₆alkyl.

[0267] Preferably R⁴ is OH, OC₁-C₆ alkyl, C₁-C₆ alkyl.

[0268] Preferably R⁴a is C₁-C₆ alkyl.

[0269] Preferably R⁵ is H or C₁-C₆ alkyl. Most preferably R⁵ is H.

[0270] The pharmaceutically acceptable salts of the compounds of thisinvention can be synthesized from the compounds of this invention whichcontain a basic or acidic moiety by conventional chemical methods.Generally, the salts of the basic compounds are prepared either by ionexchange chromatography or by reacting the free base with stoichiometricamounts or with an excess of the desired salt-forming inorganic ororganic acid in a suitable solvent or various combinations of solvents.Similarly, the salts of the acidic compounds are formed by reactionswith the appropriate inorganic or organic base.

[0271] The compounds of this invention may be prepared by employingreactions as shown in the following schemes, in addition to otherstandard manipulations that are known in the literature or exemplifiedin the experimental procedures. These schemes, therefore, are notlimited by the compounds listed nor by any particular substituentsemployed for illustrative purposes. Substituent numbering as shown inthe schemes does not necessarily correlate to that used in the claims.

Synopsis of Schemes

[0272] As shown in Scheme 1, the quinoline reagent 1-2 can besynthesized by the general procedures taught in Marsais, F; Godard, A.;Queguiner, G. J. Hetero-cyclic Chem. 1989, 26, 1589-1594). Derivativeswith varying substitution can be made by modifying this procedure anduse of standard synthetic protocols known in the art. Intermediate 1-2is then coupled with the appropriate N-protected pyrollo-compound,structure 1-4, to produce a chlorinated intermediate of structure 1-5.At least one of the R⁴ substituents would be OH or OR on the carbonadjacent to the ring nitrogen. Heating of 1-5 in aqueous acetic acidproduces the desired de-chlorinated product, 1-6. Scheme 2 shows anexample using this route to arrive at a [3,2]-pyridno-pyrole, 2-3.

[0273] As shown in Scheme 3, the α-alkyloxy pyridino-pyroles 3-1 can beconverted to the corresponding pyrimidinone analogs 3-2 by heating withaqueous HBr. Alternatively, the pyrimidinone analogs can be synthesizedvia the N-oxide intermediates 4-2 as shown in Scheme 4. Scheme 5 showsthe N-alkylation of the pyrimidinone-pyrole 3-2 to arrive at thecompounds of Formula I. Other electrophilic reagents can be employed toalkylate or acylate the nitrogen, as will be apparent to the skilledartisan.

Utility

[0274] The instant compounds are useful as pharmaceutical agents formammals, especially for humans, in the treatment of tyrosine kinasedependent diseases. Such diseases include the proliferation of tumorcells, the pathologic neovascularization (or angiogenesis) that supportssolid tumor growth, ocular neovascularization (diabetic retinopathy,age-related macular degeneration, and the like) and inflammation(psoriasis, rheumatoid arthritis, and the like).

[0275] The compounds of the instant invention may be administered topatients for use in the treatment of cancer. The instant compoundsinhibit tumor angiogenesis, thereby affecting the growth of tumors (J.Rak et al. Cancer Research, 55:4575-4580, 1995). The anti-angiogenesisproperties of the instant compounds are also useful in the treatment ofcertain forms of blindness related to retinal vascularization.

[0276] The disclosed compounds are also useful in the treatment ofcertain bone-related pathologies, such as osteosarcoma, osteoarthritis,and rickets, also known as oncogenic osteomalacia. (Hasegawa et al.,Skeletal Radiol., 28, pp.41-45, 1999; Gerber et al., Nature Medicine,Vol. 5, No. 6, pp.623-628, June 1999). And since VEGF directly promotesosteoclastic bone resorption through KDR/Flk-1 expressed in matureosteoclasts (FEBS Let. 473:161-164 (2000); Endocrinology, 141:1667(2000)), the instant compounds are also useful to treat and preventconditions related to bone resorption, such as osteoporosis and Paget'sdisease.

[0277] The claimed compounds can also be used to reduce or preventtissue damage which occurs after cerebral ischemic events, such asstroke, by reducing cerebral edema, tissue damage, and reperfusioninjury following ischemia. (Drug News Perspect 11:265-270 (1998); J.Clin. Invest. 104:1613-1620 (1999)).

[0278] The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

[0279] For oral use of a chemotherapeutic compound according to thisinvention, the selected compound may be administered, for example, inthe form of tablets or capsules, or as an aqueous solution orsuspension. In the case of tablets for oral use, carriers which arecommonly used include lactose and corn starch, and lubricating agents,such as magnesium stearate, are commonly added. For oral administrationin capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Forintramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

[0280] The compounds of the instant invention may also beco-administered with other well known therapeutic agents that areselected for their particular usefulness against the condition that isbeing treated. For example, in the case of bone-related disorders,combinations that would be useful include those with antiresorptivebisphosphonates, such as alendronate and risedronate; integrin blockers(defined further below), such as α_(v)β₃ antagonists; conjugatedestrogens used in hormone replacement therapy, such as PREMPRO®,PREMARIN®) and ENDOMETRION®; selective estrogen receptor modulators(SERMs), such as raloxifene, droloxifene, CP-336,156 (Pfizer) andlasofoxifene; cathespin K inhibitors; and ATP proton pump inhibitors.

[0281] The instant compounds are also useful in combination with knownanti-cancer agents. Such known anti-cancer agents include the following:estrogen receptor modulators, androgen receptor modulators, retinoidreceptor modulators, cytotoxic agents, antiproliferative agents,prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIVprotease inhibitors, reverse transcriptase inhibitors, and otherangiogenesis inhibitors. The instant compounds are particularly usefulwhen coadminsitered with radiation therapy. The synergistic effects ofinhibiting VEGF in combination with radiation therapy have beendescribed in the art. (see WO 00/61186). “Estrogen receptor modulators”refers to compounds which interfere or inhibit the binding of estrogento the receptor, regardless of mechanism. Examples of estrogen receptormodulators include, but are not limited to, tamoxifen, raloxifene,idoxifene, LY353381, LY117081, toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

[0282] “Androgen receptor modulators” refers to compounds whichinterfere or inhibit the binding of androgens to the receptor,regardless of mechanism. Examples of androgen receptor modulatorsinclude finasteride and other 5α-reductase inhibitors, nilutamide,flutamide, bicalutamide, liarozole, and abiraterone acetate.

[0283] “Retinoid receptor modulators” refers to compounds whichinterfere or inhibit the binding of retinoids to the receptor,regardless of mechanism. Examples of such retinoid receptor modulatorsinclude bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoicacid, α-difluoromethylomithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, N-4-carboxyphenyl retinamide,

[0284] “Cytotoxic agents” refer to compounds which cause cell deathprimarily by interfering directly with the cell's functioning or inhibitor interfere with cell myosis, including alkylating agents, tumornecrosis factors, intercalators, microtubulin inhibitors, andtopoisomerase inhibitors.

[0285] Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine) platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

[0286] Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, and BMS 188797.

[0287] Some examples of topoisomerase inhibitors are topotecan,hycaptamine, irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin,BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide,sobuzoxane, 2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine, (5a, 5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-Hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

[0288] “Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl) urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin,5-flurouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also includes monoclonal antibodies to growth factors, otherthan those listed under “angiogenesis inhibitors”, such as trastuzumab,and tumor suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

[0289] “HMG-COA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for HMG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein.

[0290] Examples of HMG-CoA reductase inhibitors that may be used includebut are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos.4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR®; see U.S. Pat.Nos. 4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL®; see U.S.Pat. Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772; 4,911,165;4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), atorvastatin(LIPITOR®; see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691;5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (Feb. 5, 1996) and U.S. Pat.Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor asused herein includes all pharmaceutically acceptable lactone andopen-acid forms (i.e., where the lactone ring is opened to form the freeacid) as well as salt and ester forms of compounds which have HMG-CoAreductase inhibitory activity, and therefor the use of such salts,esters, open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

[0291] In HMG-CoA reductase inhibitors where an open-acid form canexist, salt and ester forms may preferably be formed from the open-acid,and all such forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin. Herein, the term “pharmaceutically acceptablesalts” with respect to the HMG-CoA reductase inhibitor shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine, omithine,choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, and tris(hydroxymethyl) aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

[0292] Ester derivatives of the described HMG-CoA reductase inhibitorcompounds may act as prodrugs which, when absorbed into the bloodstreamof a warm-blooded animal, may cleave in such a manner as to release thedrug form and permit the drug to afford improved therapeutic efficacy.

[0293] “Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase). Examples of prenyl-protein transferase inhibiting compoundsinclude(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl)-2-piperazinone,5(S)-n-Butyl-1-(2-methylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone,1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine,4-{5-[4-Hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(5-chloro-2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(2-Oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-[3-(2-Oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethylbenzonitrile,18,19-dihydro-19-oxo-5H,17H-6,10:12,16-dimetheno-1H-imidazo[4,3-c][1,11,4]dioxaazacyclo-nonadecine-9-carbonitrile,(±)-19,20-Dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile,19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6,10:12,16-dimetheno-22H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile,and(±)-19,20-Dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.

[0294] Other examples of prenyl-protein transferase inhibitors can befound in the following publications and patents: WO 96/30343, WO97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO98/29119, WO 95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359,5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0 618 221,European Patent Publ. 0 675 112, European Patent Publ. 0 604 181,European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917,WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO96/05169, WO 96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO97/44350, WO 98/02436, and U.S. Pat. No. 5,532,359. For an example ofthe role of a prenyl-protein transferase inhibitor on angiogenesis seeEuropean J. of Cancer, Vol. 35, No. 9, pp.1394-1401 (1999).

[0295] Examples of HIV protease inhibitors include amprenavir, abacavir,CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir,ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632. Examples ofreverse transcriptase inhibitors include delaviridine, efavirenz,GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl.

[0296] “Angiogenesis inhibitors” refers to compounds that inhibit theformation of new blood vessels, regardless of mechanism. Examples ofangiogenesis inhibitors include, but are not limited to, tyrosine kinaseinhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1(VEGFR¹) and Flk-1/KDR (VEGFR20), inhibitors of epidermal-derived,fibroblast-derived, or platelet derived growth factors, MMP (matrixmetalloprotease) inhibitors, integrin blockers, interferon-α,interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors,including nonsteroidal anti-inflammatories (NSAIDs) like aspirin andibuprofen as well as selective cyclooxygenase-2 inhibitors likecelecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69,p. 475 (1982); Arch. Opthalmol., Vol. 108, p.573 (1990); Anat. Rec.,Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin,Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16, p.107(1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol.57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med.,Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)),carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab.Clin. Med. 105:141-145 (1985)), and antibodies to VEGF. (see, NatureBiotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature,362, 841-844 (1993); WO 00/44777; and WO 00/61186).

[0297] As described above, the combinations with NSAID's are directed tothe use of NSAID's which are potent COX-2 inhibiting agents. Forpurposes of this specification an NSAID is potent if it possess an IC50for the inhibition of COX-2 of 1 μM or less as measured by the cell ormicrosomal assay disclosed herein.

[0298] The invention also encompasses combinations with NSAID's whichare selective COX-2 inhibitors. For purposes of this specificationNSAID's which are selective inhibitors of COX-2 are defined as thosewhich possess a specificity for inhibiting COX-2 over COX-1 of at least100 fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by the cell or micromsal assay disclosed hereinunder. Suchcompounds include, but are not limited to those disclosed in U.S. Pat.No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issuedJan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat.No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr.25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No.5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, U.S. Pat. No. 5,710,140, issued Jan.20,1998, WO 94/15932, published Jul. 21, 1994, U.S. Pat. No. 5,344,991,issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S.Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790,issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995,U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No.5,932,598, issued Aug. 3, 1999, all of which are hereby incorporated byreference.

[0299] Other examples of specific inhibitors of COX-2 include thefollowing:

[0300] 3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;

[0301]3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;

[0302]3-(3,4-dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;

[0303] 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;

[0304]5,5-dimethyl-3-(3-fluorophenyl)-4-(methylsulfonyl)phenyl)-2-(5H)-furanone;

[0305] 3-(4-methylsulfonyl)phenyl-2-phenyl-5-trifluoromethylpyridine;

[0306]2-(3-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine;

[0307]2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine;

[0308]2-(4-fluorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine;

[0309]3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)-5-trifluoromethylpyridine;

[0310] 5-methyl-3-(4-methylsulfonyl)phenyl-2-phenylpyridine;

[0311] 2-(4-chlorophenyl)-5-methyl-3-(4-methylsulfonyl) phenylpyridine;

[0312] 5-methyl-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine;

[0313] 5-chloro-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine;

[0314] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-pyridinyl) pyridine;

[0315] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine;

[0316] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(4-pyridinyl) pyridine;

[0317]5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine;

[0318]2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic acidmethyl ester;

[0319]2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylicacid;

[0320] 5-cyano-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine;

[0321] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridinehydromethanesulfonate;

[0322] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridinehydrochloride;

[0323]5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridinehydrochloride;

[0324]5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine;

[0325] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridinehydromethanesulfonate;

[0326]3-(3,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0327]3-(3-fluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0328] 3-(3,5-difluorophenoxy)-5,5-dimethyl-4-(methylsulfonyl)phenyl)-SH-furan-2-one;

[0329]3-phenoxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0330]3-(2,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0331]3-(4-chlorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0332] 3-(3,4-dichlorophenoxy)-5,5-dimethyl-4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0333] 3-(4-fluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0334]3-(4-fluorophenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0335]3-(3,5-difluorophenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0336]3-phenylthio-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0337]3-(N-phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0338] 3-(N-methyl-N-phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0339]3-cyclohexyloxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0340] 3-phenylthio-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0341]3-benzyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0342]3-(3,4-difluorophenylhydroxymethyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0343]3-(3,4-difluorobenzoyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0344]3-benzoyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0345]4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-oxaspiro[4.4]non-3-en-2-one;

[0346] 4-(4-(methylsulfonyl)phenyl)-3-phenylthio-1-oxaspiro[4.4]non-3-en-2-one;

[0347] 4-(2-oxo-3-phenylthio-1-oxa-spiro[4,4]non-3-en-4-yl)benzenesulfonamide;

[0348] 3-(4-fluorobenzyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0349]3-(3,4-difluorophenoxy)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0350]3-(5-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0351]3-(2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0352] 3-(6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0353]3-(3-isoquinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0354] 3-(4-(methylsulfonyl)phenyl)-2-phenoxycyclopent-2-enone;

[0355]3-(4-(methylsulfonyl)phenyl)-2-(3,4-difluorophenoxy)cyclopent-2-enone;

[0356]5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(5-bromopyridin-2-yloxy)-5H-furan-2-one;

[0357]5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-one;

[0358]2-(3,4-difluorophenoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enone;

[0359] 3-(5-benzothiophenyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0360]5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(pyridyl-4-oxy)-5H-furan-2-one;

[0361]5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(pyridyl-3-oxy)-5H-furan-2-one;

[0362] 3-(2-methyl-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0363]3-(2-fluoro-4-trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;

[0364]3-(5-chloro-2-pyridylthio)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0365]2-(3,5-difluorophenoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enone;

[0366]3-(2-pyrimidinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0367]3-(3-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0368] 3-(3-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0369]3-(3-(1,2,5-thiadiazolyl)oxy)-4-(4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;

[0370]3-(5-isoquinolinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-SH-furan-2-one;

[0371] 3-(6-amino-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0372]3-(3-chloro-4-fluoro)phenoxy-4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;

[0373]3-(6-quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0374]3-(5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0375]3-(2-thiazolylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0376] 3-(3-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0377]5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-one;

[0378]3-(3-trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;

[0379]5,5-dimethyl-(4-(4-methylsulfonyl)phenyl)-3-(piperidine-1-carbonyl)-5-H-furan-2-one;

[0380]5,5-dimethyl-3-(2-Butoxy)-4-(4-methylsulfonylphenyl)-5H-furan-2-one;

[0381]5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(3-pentoxy)-5H-furan-2-one;

[0382]2-(5-chloro-2-pyridyloxy)-3-(4-methylsulfonyl)phenylcyclopent-2-enone;

[0383]3-(4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0384](5R)-3-(3,4-difluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0385](5R)-3-(4-chlorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0386]3-(2-methyl-3-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0387]3-(4-methyl-5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0388]3-(5-chloro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0389]3-(5-fluoro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0390]3-(3-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0391]3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-propyl-5H-furan-2-one;

[0392] 3-(N,N-diethylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0393]5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(3,5-dichloro-2-pyridyloxy)-5H-furan-2-one;

[0394](5R)-3-(4-bromophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0395](5R)-3-(4-methoxyphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0396](5R)-3-(5-chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;

[0397]3-(5-chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-propy1-5H-furan-2-one;

[0398] 3-(1-cyclopropyl-ethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one;

[0399]5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-(propoxy)-5-(2-trifluoroethyl)-5H-furan-2-one;

[0400]5(R)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one;

[0401]5,5-dimethyl-3-(2,2-dimethylpropyloxy)-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0402] 5(R)-3-(1-cyclopropyl-ethoxy)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl-5H-furan-2-one;

[0403]5(S)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl-3-(2-propoxy)-5H-furan-2-one;

[0404]3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0405]3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0406]5,5-dimethyl-3-(isobutoxy)-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0407]3-(4-bromophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0408]3-(2-quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0409]3-(2-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0410] 3-(6-benzothiazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0411] 3-(6-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0412]3-(4-quinazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0413](5R)-3-(5-fluoro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0414](5R)-3-(4-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)pheny1-5H-furan-2-one;

[0415](5R)-3-(5-fluoro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;

[0416]3-(1-isoquinolinyloxy)-5,5-dimethyl-4-(methylsulfonyl)phenyl-5H-furan-2-one;

[0417](5R)-3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;

[0418] 3-(3-fluoro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0419] (5R)-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfony1)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;

[0420](5R)-3-(5-chloro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0421]3-(3,4-difluorophenoxy)-5-methyl-5-trifluoromethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0422]3-(3,4-difluorophenoxy)-5-methyl-4-(4-(methylsulfonyl)phenyl)-5-propyl-5H-furan-2-one;

[0423]3-cyclobutyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl-5H-furan-2-one;

[0424]3-(1-indanyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;

[0425]3-(2-indanyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one;

[0426]3-cyclopentyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)5H-furan-2-one;

[0427]3-(3,3-dimethylcyclopentyloxy)-5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-5H-furan-2-one;

[0428]3-isopropoxy-5-methyl-4-(4-methylsulfonylphenyl)-5-propyl-5H-furan-2-one;

[0429]3-(2-methoxy-5-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0430]3-(5-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0431](5RS)-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;

[0432]3-(3-chloro-4-methoxyphenoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0433](5R)-3-(3-chloro-4-methoxyphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0434](5R)-3-(4-chlorophenoxy)-5-trifluoroethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0435](5R)-3-(4-bromophenoxy)-5-trifluoroethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0436]5-cyclopropylmethyl-3-(3,4-difluorophenoxy)-5-methyl-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0437](5R)-3-(3fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0438](5R)-3-(4-chloro-3-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0439](5R)-3-phenoxy-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0440](5R)-3-(4-chloro-3-methylphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0441]3-(4-chloro-3-methylphenoxy)-5-5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0442](5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;

[0443](5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-ethyl-5-methyl-5H-furan-2-one;

[0444]3-(5-chloro-6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0445]3-(5-cyclopropyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0446]3-(1-cyclopropylethoxy)-4-(4-methylsulfonyl)phenyl-5H-furan-2-one; and

[0447] 3-(cyclopropylmethoxy)-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;

[0448] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0449] Inhibitors of COX-2 that are particularly useful in the instantmethod of treatment are:

[0450] 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H-furanone; and

[0451]5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine;

[0452] or a pharmaceutically acceptable salt thereof.

[0453] General and specific synthetic procedures for the preparation ofthe COX-2 inhibitor compounds described above are found in U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, and U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, all ofwhich are herein incorporated by reference.

[0454] Compounds that have been described as specific inhibitors ofCOX-2 and are therefore useful in the present invention include, but arenot limited to, the following:

[0455] or a pharmaceutically acceptable salt thereof.

[0456] Compounds which are described as specific inhibitors of COX-2 andare therefore useful in the present invention, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference: WO 94/15932,published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued June 6, 1994,U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738,issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995,U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999.

[0457] Compounds which are specific inhibitors of COX-2 and aretherefore useful in the present invention, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference: U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No.6,020,343, issued Feb. 1, 2000, U.S. Pat. 5,409,944, issued Apr. 25,1995 , U.S. Pat. No. 5,436,265, issued Jul. 25, 1995 , U.S. Pat. No.5,536,752, issued Jul. 16, 1996 , U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, and U.S. Pat. No. 5,710,140, issuedJan. 20, 1998.

[0458] Other examples of angiogenesis inhibitors include, but are notlimited to, endostation, ukrain, ranpimase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RP14610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonyl-imino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

[0459] As used above, “integrin blockers” refers to compounds whichselectively antagonize, inhibit or counteract binding of a physiologicalligand to the α_(v)β₃ integrin, to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe αvβ5 integrin, to compounds which antagonize, inhibit or counteractbinding of a physiological ligand to both the α_(v)β₃ integrin and theα_(v)β₅ integrin, and to compounds which antagonize, inhibit orcounteract the activity of the particular integrin(s) expressed oncapillary endothelial cells. The term also refers to antagonists of theα_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The termalso refers to antagonists of any combination of α_(v)β₃, α_(v)β₅,α_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁, and α₆β₄ integrins.

[0460] Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH1382, genistein, ST1571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo [2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, ST1571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

[0461] The instant compounds are also useful, alone or in combinationwith platelet fibrinogen receptor (GP IIb/IIIa) antagonists, such astirofiban, to inhibit metastasis of cancerous cells. Tumor cells canactivate platelets largely via thrombin generation. This activation isassociated with the release of VEGF. The release of VEGF enhancesmetastasis by increasing extravasation at points of adhesion to vascularendothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, thepresent compounds can serve to inhibit metastasis, alone or incombination with GP IIb/IIIa) antagonists. Examples of other fibrinogenreceptor antagonists include abciximab, eptifibatide, sibrafiban,lamifiban, lotrafiban, cromofiban, and CT50352.

[0462] If formulated as a fixed dose, such combination products employthe compounds of this invention within the dosage range described belowand the other pharmaceutically active agent(s) within its approveddosage range. Compounds of the instant invention may alternatively beused sequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

[0463] The term “administration” and variants thereof (e.g.,“administering” a compound) in reference to a compound of the inventionmeans introducing the compound or a prodrug of the compound into thesystem of the animal in need of treatment. When a compound of theinvention or prodrug thereof is provided in combination with one or moreother active agents (e.g., a cytotoxic agent, etc.), “administration”and its variants are each understood to include concurrent andsequential introduction of the compound or prodrug thereof and otheragents.

[0464] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0465] The term “therapeutically effective amount” as used herein meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

[0466] The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

[0467] The present invention also encompasses a pharmaceuticalcomposition useful in the treatment of cancer, comprising theadministration of a therapeutically effective amount of the compounds ofthis invention, with or without pharmaceutically acceptable carriers ordiluents. Suitable compositions of this invention include aqueoussolutions comprising compounds of this invention and pharmacologicallyacceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions may be introduced into a patient's bloodstream by local bolusinjection.

[0468] When a compound according to this invention is administered intoa human subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

[0469] In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

Assays

[0470] The compounds of the instant invention described in the Exampleswere tested by the assays described below and were found to have kinaseinhibitory activity. Other assays are known in the literature and couldbe readily performed by those of skill in the art. (see, for example,Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk etal., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst.52:413-427; Nicosia et al., In Vitro 18:538-549).

VEGF Receptor Kinase Assay

[0471] VEGF receptor kinase activity is measured by incorporation ofradio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY)substrate. The phosphorylated pEY product is trapped onto a filtermembrane and the incorporation of radio-labeled phosphate quantified byscintillation counting.

Materials VEGF Receptor Kinase

[0472] The intracellular tyrosine kinase domains of human KDR (Terman,B. I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya,M. et al. Oncogene (1990) vol. 5, pp. 519-524) were cloned asglutathione S-transferase (GST) gene fusion proteins. This wasaccomplished by cloning the cytoplasmic domain of the KDR kinase as anin frame fusion at the carboxy terminus of the GST gene. Solublerecombinant GST-kinase domain fusion proteins were expressed inSpodoptera frugiperda (Sf21) insect cells (Invitrogen) using abaculovirus expression vector (pAcG2T, Pharmingen).

Lysis Buffer

[0473] 50 mM Tris pH 7.4,0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5% tritonX-100, 10% glycerol, 10 mg/mL of each leupeptin, pepstatin and aprotininand 1 mM phenylmethylsulfonyl fluoride (all Sigma).

Wash Buffer

[0474] 50 mM Tris pH 7.4,0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% tritonX-100, 10 % glycerol, 10 mg/mL of each leupeptin, pepstatin andaprotinin and 1 mM phenylmethylsulfonyl fluoride.

Dialysis Buffer

[0475] 50 mM Tris pH 7.4,0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% tritonX-100, 50% glycerol, 10 mg/mL of each leupeptin, pepstatin and aprotininand 1 mM phenylmethylsuflonyl fluoride.

10×Reaction Buffer

[0476] 200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl₂, 10 mM DTT and 5mg/mL bovine serum albumin (Sigma).

Enzyme Dilution Buffer

[0477] 50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10 % glycerol, 100mg/mL BSA.

10×Substrate

[0478] 750 μg/mL poly (glutamic acid, tyrosine; 4:1) (Sigma).

Stop Solution

[0479] 30% trichloroacetic acid, 0.2 M sodium pyrophosphate (bothFisher).

Wash Solution

[0480] 15% trichloroacetic acid, 0.2 M sodium pyrophosphate.

Filter Plates

[0481] Millipore #MAFC NOB, GF/C glass fiber 96 well plate.

Method A. Protein Purification

[0482] 1. Sf21 cells were infected with recombinant virus at amultiplicity of infection of 5 virus particles/ cell and grown at 27° C.for 48 hours.

[0483] 2. All steps were performed at 4° C. Infected cells wereharvested by centrifugation at 1000×g and lysed at 4° C. for 30 minuteswith 1/10 volume of lysis buffer followed by centrifugation at 100,000×gfor 1 hour. The supernatant was then passed over a glutathione Sepharosecolumn (Pharmacia) equilibrated in lysis buffer and washed with 5volumes of the same buffer followed by 5 volumes of wash buffer.Recombinant GST-KDR protein was eluted with wash buffer/10 mM reducedglutathione (Sigma) and dialyzed against dialysis buffer.

B. VEGF Receptor Kinase Assay

[0484] 1. Add 5 μl of inhibitor or control to the assay in 50% DMSO.

[0485] 2. Add 35 μl of reaction mix containing 5 μl of 10×reactionbuffer, 5 μl 25 mM ATP/10 μCi [³³P]ATP (Amersham), and 5 μl10×substrate.

[0486] 3. Start the reaction by the addition of 10 μl of KDR (25 nM) inenzyme dilution buffer.

[0487] 4. Mix and incubate at room temperature for 15 minutes.

[0488] 5. Stop by the addition of 50 μl stop solution.

[0489] 6. Incubate for 15 minutes at 4° C.

[0490] 7. Transfer a 90 μl aliquot to filter plate.

[0491] 8. Aspirate and wash 3 times with wash solution.

[0492] 9. Add 30 μl of scintillation cocktail, seal plate and count in aWallac Microbeta scintillation counter.

Human Umbilical Vein Endothelial Cell Mitogenesis Assay

[0493] Expression of VEGF receptors that mediate mitogenic responses tothe growth factor is largely restricted to vascular endothelial cells.Human umbilical vein endothelial cells (HU Cs) in culture proliferate inresponse to VEGF treatment and can be used as an assay system toquantify the effects of KDR kinase inhibitors on VEGF stimulation. Inthe assay described, quiescent HUVEC monolayers are treated with vehicleor test compound 2 hours prior to addition of VEGF or basic fibroblastgrowth factor (bFGF). The mitogenic response to VEGF or bFGF isdetermined by measuring the incorporation of [³H]thymidine into cellularDNA.

Materials HUVECs

[0494] HUVECs frozen as primary culture isolates are obtained fromClonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM;Clonetics) and are used for mitogenic assays at passages 3-7.

Culture Plates

[0495] NUNCLON 96-well polystyrene tissue culture plates (NUNC #167008).

Assay Medium

[0496] Dulbecco's modification of Eagle's medium containing 1 g/nLglucose (low-glucose DMEM; Mediatech) plus 10% (v/v) fetal bovine serum(Clonetics).

Test Compounds

[0497] Working stocks of test compounds are diluted serially in 100%dimethylsulfoxide (DMSO) to 400-fold greater than their desired finalconcentrations. Final dilutions to 1×concentration are made directlyinto Assay Medium immediately prior to addition to cells.

10×Growth Factors

[0498] Solutions of human VEGF165 (500 ng/mL; R&D Systems) and bFGF (10ng/mL; R&D Systems) are prepared in Assay Medium.

10×[³H]Thymidine

[0499] [Methyl-³H]Thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80uCi/mL in low-glucose DMEM.

Cell Wash Medium

[0500] Hank's balanced salt solution (Mediatech) containing 1 mg/mLbovine serum albumin (Boehringer-Mannheim).

Cell Lysis Solution

[0501] 1 N NaOH, 2% (w/v) Na₂CO₃.

Method

[0502] 1. HUVEC monolayers maintained in EGM are harvested bytrypsinization and plated at a density of 4000 cells per 100 μL AssayMedium per well in 96-well plates. Cells are growth-arrested for 24hours at 37° C. in a humidified atmosphere containing 5% CO₂.

[0503]2. Growth-arrest medium is replaced by 100 μL Assay Mediumcontaining either vehicle (0.25% [v/v]DMSO) or the desired finalconcentration of test compound. All determinations are performed intriplicate. Cells are then incubated at 37° C./5% CO₂ for 2 hours toallow test compounds to enter cells.

[0504] 3. After the 2-hour pretreatment period, cells are stimulated byaddition of 10 μL/well of either Assay Medium, 10×VEGF solution or10×bFGF solution. Cells are then incubated at 37° C./5% CO₂.

[0505] 4. After 24 hours in the presence of growth factors,10×[³H]Thymidine (10 μL/well) is added.

[0506] 5. Three days after addition of [³H]thymidine, medium is removedby aspiration, and cells are washed twice with Cell Wash Medium (400μL/well followed by 200 μL/well). The washed, adherent cells are thensolubilized by addition of Cell Lysis Solution (100 μL/well) and warmingto 37° C. for 30 minutes. Cell lysates are transferred to 7-mL glassscintillation vials containing 150 μL of water. Scintillation cocktail(5 ml/vial) is added, and cell-associated radioactivity is determined byliquid scintillation spectroscopy.

[0507] Based upon the foregoing assays the compounds of formula I areinhibitors of VEGF and thus are useful for the inhibition ofangiogenesis, such as in the treatment of ocular disease, e.g., diabeticretinopathy and in the treatment of cancers, e.g., solid tumors. Theinstant compounds inhibit VEGF-stimulated mitogenesis of human vascularendothelial cells in culture with IC50 values between 0.01-5.0 μM. Thesecompounds also show selectivity over related tyrosine kinases (e.g.,FGFR1 and the Src family; for relationship between Src kinases and VEGFRkinases, see Eliceiri et al., Molecular Cell, Vol. 4, pp.915-9²⁴, Dec.1999).

EXAMPLES

[0508] Examples provided are intended to assist in a furtherunderstanding of the invention. Particular materials employed, speciesand conditions are intended to be further illustrative of the inventionand not limiting of the reasonable scope thereof.

Example 1 3-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one

[0509]

Step 1: Synthesis of 2-chloro-3-iodo-quinoline (Intermediate A)

[0510]

[0511] A suspension of 3-(2-chloro)-quinolineboronic acid (5.05 g, 24.3mmol, 1 equiv, prepared by the method of Marsais, F; Godard, A.;Queguiner, G. J. Heterocyclic Chem. 1989, 26, 1589-1594) andN-iodosuccinimide (5.48 g, 24.4 mmol, 1.00 equiv) in acetonitrile (300mL) was stirred at 23° C. in the dark for 20 hours. The reaction mixturewas concentrated to dryness, and the resulting yellow solid waspartitioned between saturated aqueous sodium bicarbonate solution anddichloromethane. The organic layer was washed with water, then driedover magnesium sulfate and concentrated to give2-chloro-3-iodo-quinoline (intermediate A) as a pale yellow solid.

[0512]¹H NMR (400 MHz, CDCl₃) δ8.67 (s, 1H), 7.99 (br d, 1H, J═8.4 Hz),7.75 (br t, 1H, J═7.7 Hz), 7.72 (br d, 1H, J═7.8 Hz), 7.57 (br t, 1H,J═7.6 Hz).

[0513] Step 2: Synthesis of Intermediate B

Intermediate B

[0514] A solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (0.930 g, 6.28mmol, 1 equiv, prepared by the method of Mazeas, D.; Guillaumet, G.;Viaud, M-C Heterocycles 1999, 50, 1065-1080), di-tert-butyl dicarbonate(1.64 g, 4.05 mmol, 1.20 equiv), and 4-dimethylaminopyridine (10 mg,0.082 mmol, 0.013 equiv) in dichloromethane (30 mL) was stirred at 23°C. for 1 hour. The reaction mixture was concentrated, and the residuewas purified by flash column chromatography (100% hexanes initially,grading to 30% ethyl acetate in hexanes) to afford intermediate B as acolorless oil.

[0515]¹H NMR (300 MHz, CDCl₃) δ8.24 (br d, 1H, J═9.0 Hz), 7.72 (br d,1H, J═3.4 Hz), 6.69 (d, 1H, J═9.0 Hz), 6.63 (d, 1H, J═3.9 Hz), 3.99 (s,3H), 1.67 (s, 9H).

Step 3: Synthesis of Intermediate C

[0516]

Intermediate C

[0517] Step 1: A solution of tert-butyllithium in pentane (1.7 M, 3.95mL, 6.72 mmol, 1.20 equiv) was added to a solution of intermediate B(1.39 g, 5.60 mmol, 1 equiv) in THF (70 mL) at −78° C. The orangesolution was stirred for 15 min, then a solution of trimethyltinchloride (2.23 g, 11.2 mmol, 2.00 equiv) in THF (4.0 mL) was added. Thereaction mixture was warmed to 23° C., then partitioned between aqueouspH 7 phosphate buffer and a 1:1 mixture of ethyl acetate and hexane (100mL). The organic layer was dried over sodium sulfate and concentrated.

[0518] Step 2: A deoxygenated solution of this residue, intermediate A(0.800 g, 2.76 mmol, 0.500 equiv), tetrakis(triphenylphosphine)palladium(0.160 g, 0.140 mmol, 0.025 equiv), and cuprous iodide (0.053 g, 0.28mmol, 0.05 equiv) in dioxane (40 mL) was heated at 90° C. for 20 hours.The reaction mixture was cooled, then partitioned between brine (150 mL)and ethyl acetate (150 mL). The organic layer was dried over sodiumsulfate, then concentrated. The residue was purified by flash columnchromatography (100% hexanes initially, grading to 30% ethyl acetate inhexanes) to afford intermediate C. as a light yellow foam.

[0519]¹H NMR (300 MHz, CDCl₃) δ8.44 (d, 1H, J═9.2 Hz), 8.18 (s, 1H),8.08 (d, 1H, J═8.5 Hz), 7.88 (d, 1H, J═8.2 Hz), 7.79 (ddd, 1H, J═8.5,7.0, 1.5 Hz), 7.63 (ddd, 1H, J═8.5, 7.0, 1.5 Hz), 6.78 (d, 1H, J═8.8Hz), 6.72 (s, 1H), 4.02 (s, 3H), 1.27 (s, 9H),

[0520] Step 4: Synthesis of3-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one

[0521] A solution of intermediate C (900 mg, 2.20 mmol) was heated in a1:1 mixture of acetic acid and water (50 mL) at reflux for 16 hours. Thereaction mixture was concentrated, and the residue was partitionedbetween aqueous saturated sodium bicarbonate solution (150 mL) and hotethyl acetate (3×200 mL). The combined organic layers were dried oversodium sulfate and concentrated. The residue was suspended in ethylether (200 mL), filtered, then air-dried to give the titled compound asa yellow solid.

[0522]¹H NMR (300 MHz, (CD₃)₂SO) δ12.23 (s, 1H), 11.75 (s, 1H), 8.58 (s,1H), 7.86 (br d, 1H, J═9.2 Hz), 7.75 (br d, 1H, J═7.6, Hz), 7.54 (br t,1H, J═7.8 Hz), 7.39 (d, 1H, J═8.2 Hz), 7.26 (br t, 1H, J═7.6 Hz), 7.18(br s, 1H), 6.57 (d, 1H, J═8.5 Hz), 3.88 (s, 3H). HRMS (electrosprayFTI/ICR) calcd for C17H14N3O2 [M+H]⁺292.1081, found 292.1059.

[0523] Examples 2-4 were synthesized in analogous fashion to Example 1starting from the corresponding azaindoles prepared by the method ofHands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.;Wright, S. H. B Synthesis 1996, 887-882.

Example 2 3-(5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-quinolin-2-one

[0524]

Step 1: Synthesis of Intermediate D

[0525]

Intermediate D

[0526] A solution of 5-methoxy-1H-pyrrolo[2,3-c]pyridine (190 mg, 1.28mmol, 1 equiv, prepared by the method of Mazeas, D.; Guillaumet, G.;Viaud, M-C Heterocycles 1999, 50, 1065-1080), di-tert-butyl dicarbonate(336 mg, 1.54 mmol, 1.20 equiv), and 4-dimethylaminopyridine (10 mg,0.082 mmol, 0.064 equiv) in dichloromethane (20 mL) was stirred at 23°C. for 2 hours. The reaction mixture was concentrated, and the residuewas purified by flash column chromatography (100% hexanes initially,grading to 20% ethyl acetate in hexanes) to afford intermediate E as acolorless oil which solidified upon standing (180 mg, 56%).

[0527]¹H NMR (300 MHz, CDCl₃) δ8.89 (br s, 1H), 7.70 (br d, 1H, J═4.0Hz), 6.86 (s, 1H), 6.48 (d, 1H, J═3.9 Hz), 3.98 (s, 3H), 1.68 (s, 9H).

Step 2: Synthesis of3-(5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-quinolin-2-one

[0528] Step 1: A solution of tert-butyllithium in pentane (1.7 M, 0.45mL, 0.77 mmol, 1.20 equiv) was added to a solution of intermediate D(160 mg, 0.644 mmol, 1 equiv) in THF (15 mL) at −78° C. Thebright-yellow solution was stirred for 10 min, then trimethylborate(0.144 mL, 1.29 mmol, 2.00 equiv) was added. The reaction mixture waswarmed to 0° C., then partitioned between aqueous half-saturatedammonium chloride solution and ethyl acetate (2×75 mL). The organiclayer was dried over sodium sulfate and concentrated to give a whitesolid (160 mg).

[0529] Step 2: A deoxygenated solution of this solid, intermediate A(150 mg, 0.51 mmol, 1.0 equiv), tetrakis(triphenylphosphine)palladium(30 mg, 0.026 mmol, 0.05 equiv), and potassium phosphate (327 mg, 1.54mmol, 3.00 equiv) in dioxane (15 mL) was heated at reflux for 20 hours.The reaction mixture was cooled, then partitioned between water (75 mL)and ethyl acetate (2×75 mL). The organic layer was dried over sodiumsulfate, then concentrated. The residue was passed through a column offlash-grade silica gel (40% EtOAc in hexanes initially, grading to 100%EtOAc). The fractions containing primarily the desired coupled productwere concentrated.

[0530] Step 3: A solution of this residue in a 1:1 mixture of aceticacid and water was heated at reflux for 20 hours. The reaction mixturewas concentrated, and the residue was purified by reverse-phase columnchromatography (5% acetonitrile in water initially, grading to 100%acetonitrile). The desired fractions were concentrated, and the residuewas partitioned between saturated aqueous sodium bicarbonate solutionand ethyl acetate. The organic layer was dried over sodium sulfate andconcentrated to afford the titled compound as a yellow solid.

[0531] hu 1H NMR (400 MHz, (CD₃)₂SO) δ12.22 (s, 1H), 12.00 (s, 1H), 8.62(s, 1H), 8.49 (s, 1H), 7.74 (br d, 1H, J═7.7 Hz), 7.53 (br t, 1H, J═7.7Hz), 7.37 (br d, 1H, J═8.2 Hz), 7.23 (br t, 1H, J═7.5 Hz), 7.12 (s, 1H),6.84 (s, 1H), 3.84 (s, 3H). HRMS (electrospray FT/ICR) calcd forC17H14N3O2[M+H]⁺292.1081, found 292.1068.

Example 33-(5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one

[0532]

[0533] A solution of the product from Example 1 (100 mg, 0.343 mmol) inaqueous 48% HBr solution was heated at reflux for 20 hours. The reactionmixture was cooled and the yellow solid which had precipitated wasfiltered and washed with aqueous 1 N hydrochloric acid solution. Thefiltered solid was then dried under vacuum to afford the titled productas a yellow solid.

[0534]¹H NMR (300 MHz, (CD₃)₂SO) δ14.20 (br s, 1H), 12.51 (s, 1H), 12.40(s, 1H), 8.81 (s, 1H), 8.29 (br d, 1H, J═9.2 Hz), 7.81 (br d, 1H, J═7.9Hz), 7.60 (br t, 1H, J═7.0 Hz), 7.41 (d, 1H, J═8.2 Hz), 7.30 (br t, 1H,J═7.6 Hz), 7.14 (br s, 1H), 6.70 (d, 1H, J═8.8Hz).

Example 4

[0535] 3-(5-oxo-5,6-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-quinolin-2-one

[0536] The titled compound can be made by the reaction of thecorresponding methyl ether with HBr according to the procedure inExample 3 above.

Example 5

[0537]3-(4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-quinolin-2-one

[0538] The titled compound can be made via oxidation of the product fromExample 3 followed by rearrangement (see Scheme 4).

Example 6

[0539]3-(4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one

[0540] Sodium tert-butoxide (10 mg, 0.11 mmol, 1.0 equiv) andiodomethane (13 μL, 0.22 mmol, 2.0 equiv) were added sequentially to asuspension of the product from Example 3 (30 mg, 0.11 mmol, 1 equiv) inTHF (10 mL) at 23° C. The reaction mixture was stirred for 20 hours.Additional sodium tert-butoxide (20 mg, 0.22mmol, 2.0 equiv) andiodomethane (26 μL, 0.44 mmol, 4.0 equiv) were added in 2 equal portionsover 1 hour, and then the reaction mixture was allowed to stir anadditional 1 hour. Water (5 mL) was added, and the resulting mixture wasconcentrated to a volume of 2 mL. The mixture was purified by reversephase HPLC to afford the titled compound as a yellow solid.

[0541]¹H NMR (300 MHz, (CD₃)₂SO) δ12.28 (s, 1H), 11.94 (s, 1H), 8.56 (s,1H), 7.78 (d, 1H, J═9.5 Hz), 7.73 (br d, 1H, J═7.9 Hz), 7.53 (br t, 1H,J═7.0 Hz), 7.38 (br d, 1H, J═8.2Hz), 7.26 (br t, 1H, J═7.3 Hz), 7.03 (brd, J═1.5Hz), 6.18 (d, 1H, J═9.2 Hz).

[0542] Examples 7-9 were synthesized in analogous fashion to Example 1starting from the corresponding azaindoles prepared by the method ofHands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.;Wright, S. H. B Synthesis 1996, 887-882. The products can be convertedto the N-alkylated compounds of Formula I via the procedure in Scheme 4followed by alkylation as in Scheme 5, or by other procedures readilyavailable in the chemical literature.

Example 7 3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-quinolin-2-one

[0543]

[0544]¹H NMR (400 MHz, (CD₃)₂SO) δ12.26 (s, 1H), 12.03 (s, 1H), 8.89 (brs, 1H), 8.70 (br s, 1H), 8.09 (br d, 1H, J═5.0 Hz), 7.78 (br d, 1H,J═7.7 Hz), 7.57 (br t, 1H, J═8.0 Hz), 7.53 (br d, 1H, J═5.3 Hz), 7.40(br d, 1H, J═8.3 Hz), 7.31 (br s, 1H), 7.28 (brt, 1H, J═7.6 Hz).

Example 8 3-(1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-quinolin-2-one

[0545]

[0546]¹H NMR (400 MHz, (CD₃)₂SO) δ12.23 (s, 1H), 11.97 (s, 1H), 8.87 (brs, 1H), 8.61 (s, 1H), 8.18 (br s, 1H), 7.75 (br d, 1H, J═7.7 Hz), 7.55(br t, 1H, J═8.0 Hz), 7.50 (br s, 1H), 7.45 (br s, 1H), 7.39 (br d, 1H,J═8.2 Hz), 7.27 (br t, 1H, J═7.6 Hz).

Example 9

[0547] 3-(1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one

[0548]¹H NMR (400 MHz, (CD30D) δ8.62 (s, 1H), 8.31 (dd, 1H, J═4.7, 1.3Hz), 7.92 (br d, 1H, J═8.2 Hz), 7.81 (br d, 1H, J═7.8 Hz), 7.58 (br t,1H, J═7.6 Hz), 7.40 (br, d, 1H, J═8.0 Hz), 7.34 (br s, 1H), 7.31 (br t,1H, J═8.0 Hz), 7.18 (dd, 1H, J═8.2, 4.7 Hz). HRMS (electrospray FT/ICR)calcd for C16H11N3O[M+H]⁺262.0975, found 262.0975.

What is claimed is:
 1. A compound of Formula I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Qis S, O, or —E═D—;

is selected from the following:

a is 0 or 1; b is 0 or 1; s is 1 or 2; m is 0, 1, or 2; E═D is C═N, N═C,or C═C; R¹, R^(1a), R⁴ and R⁵ are independently selected from: 1) H, 2)(C═O)_(a)O_(b)C₁-C₁₀ alkyl, optionally substituted with one to threesubstituents selected from R⁶, 3) (C═O)_(a)O_(b)aryl, optionallysubstituted with one to three substituents selected from R⁶, 4)(C═O)_(a)O_(b)C₂-C₁₀ alkenyl, optionally substituted with one to threesubstituents selected from R⁶, 5) (C═O)_(a)O_(b)C₂-C₁₀ alkynyl,optionally substituted with one to three substituents selected from R⁶,6) SO_(m)C₁-C₁₀ alkyl, optionally substituted with one to threesubstituents selected from R⁶, 7) SO_(m)aryl, optionally substitutedwith one to three substituents selected from R⁶, 8) CO₂H, 9) halo, 10)CN, 11) OH, 12) O_(b)C₁-C₆ perfluoroalkyl, and 13) (C═O)_(a)NR⁷R⁸; R²and R³ are independently selected from the group consisting of: 1) H, 2)(C═O)O_(a)C₁-C₁₀ alkyl, 3) (C═O)O_(a)aryl, 4) C₁-C₁₀ alkyl, 5)SO_(m)C₁-C₁₀ alkyl, 6) SO_(m)aryl, 7) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl, 8)(C═O)_(a)O_(b)C₂-C₁₀ alkynyl, and 9) aryl, said alkyl, aryl, alkenyl andalkynyl is optionally substituted with one to three substituentsselected from R⁶; R^(4a) is selected from the group consisting of: 1)(C═O)O_(a)C₁-C₁₀ alkyl, 2) (C═O)O_(a)aryl, 3) C₁-C₁₀ alkyl, 4)SO_(m)C₁-C₁₀ alkyl, 5) SO_(m)aryl, 6) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl, 7)(C═O)_(a)O_(b)C₂-C₁₀ alkynyl, and 8) aryl, said alkyl, aryl, alkenyl andalkynyl is optionally substituted with one to three substituentsselected from R⁶; R⁶ is: 1) H, 2) (C═O)_(a)O_(b)C₁-C₆ alkyl, 3)(C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a), 4) C₂-C₁₀ alkenyl, 5) C₂-C₁₀ alkynyl,6) heterocyclyl, optionally substituted with one to three substituentsselected from R^(6a), 7) CO₂H, 8) halo, 9) CN, 10) OH, 11) oxo, 12)O_(b)C₁-C₆ perfluoroalkyl, or 13) NR⁷R⁸; R^(6a) is: 1) H, 2) SO_(m)aryl,3) SO_(m)C₁-C₆ alkyl, 4) (C═O)_(a)O_(b)C₁-C₆ alkyl, 5)(C═O)_(a)O_(b)aryl, 6) C₂-C₁₀ alkenyl, 7) C₂-C₁₀ alkynyl, 8)heterocyclyl, 9) CO₂H, 10) halo, 11) CN, 12) OH, 13) oxo, 14) O_(b)C₁-C₆perfluoroalkyl, or 15) N(C₁-C₆ alkyl)₂; R⁷ and R⁸ are independentlyselected from: 1) H, 2) (C═O)O_(b)C₁-C₁₀ alkyl, optionally substitutedwith one to three substituents selected from R^(6a), 3) (C═O)O_(b)aryl,optionally substituted with one to three substituents selected fromR^(6a), 4) C₁-C₁₀ alkyl, optionally substituted with one to threesubstituents selected from R^(6a), 5) aryl, optionally substituted withone to three substituents selected from R^(6a), 6) C₂-C₁₀ alkenyl,optionally substituted with one to three substituents selected fromR^(6a), 7) C₂-C₁₀ alkynyl, optionally substituted with one to threesubstituents selected from R^(6a), and 8) heterocyclyl, or R⁷ and R⁸ canbe taken together with the nitrogen to which they are attached to form a5-7 membered heterocycle containing, in addition to the nitrogen, one ortwo additional heteroatoms selected from N, O and S, said heterocycleoptionally substituted with one to three substituents selected fromR^(6a).
 2. The compound of claim 1 , wherein Q is E═D.
 3. The compoundof claim 2 , wherein E═D is C═C.
 4. The compound of claim 3 , whereinR¹, R^(1a), R⁴ and R⁵ are independently selected from: 1) H, 2)(C═O)_(a)O_(b)C₁-C₆ alkyl, optionally substituted with one to threesubstituents selected from R⁶, 3) (C═O)_(a)O_(b)aryl, optionallysubstituted with one to three substituents selected from R⁶, 4)(C═O)_(a)O_(b)C₂-C₆ alkenyl, optionally substituted with one to threesubstituents selected from R⁶, 5) CO₂H, 6) halo, 7) CN, 8) OH, 9)O_(b)C₁-C₃ perfluoroalkyl, and 10) (C═O)_(a)NR⁷R⁸; R² and R³ areindependently selected from the group consisting of: 1) H, 2)(C═O)O_(a)C₁-C₆ alkyl, and 3) C₁-C₆ alkyl; R^(4a) is (C═O)O_(a)C₁-C₆alkyl or C₁-C₆ alkyl; R⁶ is: 1) H, 2) (C═O)_(a)O_(b)C₁-C₆ alkyl, 3)(C═O)_(a)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a), 4) C₂-C₆ alkenyl, 5) heterocyclyl,optionally substituted with one to three substituents selected fromR^(6a), 6) CO₂H, 7) halo, 8) CN, 9) OH, 10) oxo, 11) O_(b)C₁-C₃perfluoroalkyl, or 12) NR⁷R⁸; R^(6a) is: 1) H, 2) SO_(m)aryl, 3)SO_(m)C₁-C₆ alkyl, 4) (C═O)_(a)O_(b)C₁-C₆ alkyl, 5) (C═O)_(a)O_(b)aryl,6) C₂-C₆ alkenyl, 7) heterocyclyl, 8) CO₂H, 9) halo, 10) CN, 11) OH, 12)oxo, 13) O_(b)C₁-C₃ perfluoroalkyl, or 14) N(C₁-C₆ alkyl)₂; R⁷ and R⁸are independently selected from: 1) H, 2) (C═O)O_(b)C₁-C₆ alkyl,optionally substituted with one to three substituents selected fromR^(6a), 3) (C═O)O_(b)aryl, optionally substituted with one to threesubstituents selected from R^(6a), 4) C₁-C₆ alkyl, optionallysubstituted with one to three substituents selected from R^(6a), 5)aryl, optionally substituted with one to three substituents selectedfrom R^(6a), 6) C₂-C₆ alkenyl, optionally substituted with one to threesubstituents selected from R^(6a), and 7) heterocyclyl, or R⁷ and R⁸ canbe taken together with the nitrogen to which they are attached to form a5-7 membered heterocycle containing, in addition to the nitrogen, one ortwo additional heteroatoms selected from N, O and S, said heterocycleoptionally substituted with one to three substituents selected fromR^(6a).
 5. The compound of claim 3 , wherein a is 0 or 1; b is 0 or 1; sis 1; R¹ and R⁴ are independently selected from: 1) H, 2)(C═O)_(a)O_(b)C₁-C₆ alkyl, optionally substituted with one to threesubstituents selected from R⁶, 3) (C═O)_(a)O_(b)aryl, optionallysubstituted with one to three substituents selected from R⁶, 4)(C═O)_(a)O_(b)C₂-C₆ alkenyl, optionally substituted with one to threesubstituents selected from R⁶, 5) (C═O)_(a)O_(b)C₂-C₆ alkynyl,optionally substituted with one to three substituents selected from R⁶,6) CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₃ perfluoroalkyl, and 11)(C═O)_(a)NR⁷R⁸; R² and R³ are independently selected from H and methyl;R^(4a) is methyl; R⁵ and R^(1a) are H; R⁶ is: 1) H, 2)(C═O)_(a)O_(b)C₁-C₆ alkyl,═O)_(a)O_(b)aryl, optionally substituted withone to three substituents selected from R^(6a),C₂-C₁₀ alkenyl, 3) C₂-C₁₀alkynyl, 4) heterocyclyl, optionally substituted with one to threesubstituents selected from R^(6a), 5) CO₂H, 6) halo, 7) CN, 8) OH, 9)oxo, 10) O_(b)C₁-C₃ perfluoroalkyl, or 11) NR⁷R⁸; R^(6a) is: 1) H, 2)SO_(m)aryl, 3) SO_(m)C₁-C₆ alkyl, 4) (C═O)_(a)O_(b)C₁-C₆ alkyl, 5)(C═O)_(a)O_(b)aryl, 6) C₂-C₁₀ alkenyl, 7) C₂-C₁₀ alkynyl, 8)heterocyclyl, 9) CO₂H, 10) halo, 11) CN, 12) OH, 13) oxo, 14) O_(b)C₁-C₃perfluoroalkyl, or 15) N(C₁-C₆ alkyl)₂; R⁷ and R⁸ are independentlyselected from: 1) H, 2) (C═O)O_(b)C₁-C₆ alkyl, optionally substitutedwith one to three substituents selected from R^(6a), 3) (C═O)O_(b)aryl,optionally substituted with one to three substituents selected fromR^(6a), 4) C₁-C₁₀ alkyl, optionally substituted with one to threesubstituents selected from R^(6a), 5) aryl, optionally substituted withone to three substituents selected from R^(6a), 6) C₂-C₆ alkenyl,optionally substituted with one to three substituents selected fromR^(6a), 7) C₂-C₆ alkynyl, optionally substituted with one to threesubstituents selected from R^(6a), and 8) heterocyclyl, or R⁷ and R⁸ canbe taken together with the nitrogen to which they are attached to form apiperidinyl, piperazinyl, morpholinyl or pyrrolidinyl group, optionallysubstituted with one or two substituents selected from R^(6a).
 6. Acompound which is3-(4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-oneor a pharmaceutically acceptable salt or stereoisomer thereof.
 7. Apharmaceutical composition which is comprised of a compound inaccordance with claim 1 and a pharmaceutically acceptable carrier.
 8. Amethod of treating or preventing cancer in a mammal in need of suchtreatment which is comprised of administering to said mammal atherapeutically effective amount of a compound of claim 1 .
 9. A methodof treating cancer or preventing cancer in accordance with claim 8wherein the cancer is selected from cancers of the brain, genitourinarytract, lymphatic system, stomach, larynx and lung.
 10. A method oftreating or preventing cancer in accordance with claim 8 wherein thecancer is selected from histiocytic lymphoma, lung adenocarcinoma, smallcell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma.11. A method of treating or preventing a disease in which angiogenesisis implicated, which is comprised of administering to a mammal in needof such treatment a therapeutically effective amount of a compound ofclaim 1 .
 12. A method in accordance with claim 11 wherein the diseaseis an ocular disease.
 13. A method of treating or preventing retinalvascularization which is comprised of administering to a mammal in needof such treatment a therapeutically effective amount of compound ofclaim 1 .
 14. A method of treating or preventing diabetic retinopathywhich is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of compound of claim 1 .15. A method of treating or preventing age-related macular degenerationwhich is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of claim 1 .16. A method of treating or preventing inflammatory diseases whichcomprises administering to a mammal in need of such treatment atherapeutically effective amount of a compound of claim 1 .
 17. A methodaccording to claim 16 wherein the inflammatory disease is selected fromrheumatoid arthritis, psoriasis, contact dermatitis and delayedhypersensitivity reactions.
 18. A method of treating or preventing atyrosine kinase-dependent disease or condition which comprisesadministering a therapeutically effective amount of a compound of claim1 .
 19. A pharmaceutical composition made by combining the compound ofclaim 1 and a pharmaceutically acceptable carrier.
 20. A process formaking a pharmaceutical composition which comprises combining a compoundof claim 1 with a pharmaceutically acceptable carrier.
 21. A method oftreating or preventing bone associated pathologies selected fromosteosarcoma, osteoarthritis, and rickets which comprises administeringa therapeutically effective amount of a compound of claim 1 .
 22. Thecomposition of claim 7 further comprising a second compound selectedfrom: 1) an estrogen receptor modulator, 2) an androgen receptormodulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) anantiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7)an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) areverse transcriptase inhibitor, and 10) another angiogenesis inhibitor.23. The composition of claim 22 , wherein the second compound is anotherangiogenesis inhibitor selected from the group consisting of a tyrosinekinase inhibitor, an inhibitor of epidermal-derived growth factor, aninhibitor of fibroblast-derived growth factor, an inhibitor of plateletderived growth factor, an MMP inhibitor, an integrin blocker,interferon-a, interleukin-12, pentosan polysulfate, a cyclooxygenaseinhibitor, carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, and an antibody to VEGF.
 24. The composition of claim 22 ,wherein the second compound is an estrogen receptor modulator selectedfrom tamoxifen and raloxifene.
 25. A method of treating cancer whichcomprises administering a therapeutically effective amount of a compoundof claim 1 in combination with radiation therapy.
 26. A method oftreating or preventing cancer which comprises administering atherapeutically effective amount of a compound of claim 1 in combinationwith a compound selected from: 1) an estrogen receptor modulator, 2) anandrogen receptor modulator, 3) retinoid receptor modulator, 4) acytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-proteintransferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIVprotease inhibitor, 9) a reverse transcriptase inhibitor, and 10)another angiogenesis inhibitor.
 27. A method of treating cancer whichcomprises administering a therapeutically effective amount of a compoundof claim 1 in combination with radiation therapy and a compound selectedfrom: 1) an estrogen receptor modulator, 2) an androgen receptormodulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) anantiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7)an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) areverse transcriptase inhibitor, and 10) another angiogenesis inhibitor.28. A method of treating or preventing cancer which comprisesadministering a therapeutically effective amount of a compound of claim1 and paclitaxel or trastuzumab.
 29. A method of treating or preventingcancer which comprises administering a therapeutically effective amountof a compound of claim 1 and a GPIIb/IIIa antagonist.
 30. The method ofclaim 29 wherein the GPIIb/IIIa antagonist is tirofiban.
 31. A method ofreducing or preventing tissue damage following a cerebral ischemic eventwhich comprises administering a therapeutically effective amount of acompound of claim 1 .
 32. A method of treating or preventing cancerwhich comprises administering a therapeutically effective amount of acompound of claim 1 in combination with a COX-2 inhibitor.